Epigenetic modifications involving ncRNAs in digestive system cancers: focus on histone modification

Abstract

In recent years, epigenetic modifications have been strongly linked to tumor development, with histone modifications representing a key epigenetic mechanism. In addition, non-coding RNAs (ncRNAs) play a critical role in regulating cancer-related pathways. The abnormal interaction between histone modifications and ncRNAs, both pivotal epigenetic regulators, has been widely observed across various cancer types. Here, we systematically explore the molecular mechanisms through which histone modifications and ncRNAs contribute in the pathogenesis of digestive system cancers, and aberrant ncRNA-mediated histone modifications manipulate various biological behaviors of tumor cells including proliferation, migration, angiogenesis, etc. In addition, we provide new insights into diagnostic, prognostic markers, therapeutic targets and chemoradiation resistance for digestive system cancers from the epigenetic perspective.

Introduction

Digestive system cancers (DSCs) represent a substantial proportion of all cancers, and continue to be a major global public health concern. As stated by Global Cancer Statistics 2020, DSCs account for approximately 50% of all cancers worldwide, including nearly 6 million cases of malignant tumors of the digestive system [1]. DSCs include hepatocellular carcinoma (HCC), colorectal carcinoma (CRC), gastric carcinoma (GC), pancreatic carcinoma (PC), esophageal carcinoma (EC), head and neck squamous cell carcinoma (HNSCC), tongue and oral squamous cell carcinoma (TSCC), and gallbladder cancer. The primary treatment options for DSCs are radiotherapy and chemotherapy [2], while the insidious onset of digestive system tumors and the lack of specific symptoms and signs often result in poor treatment outcomes [3], Consequently, recurrence and metastasis rates remain high, and the overall prognosis for patients is unfavorable [4]. Thus, the development of new treatment methods for patients with digestive system cancers is an urgent and unmet clinical need.

In the last 30 years, numerous forms of RNA have been identified by researchers, but ncRNA—the kind that isn't involved in creating proteins—is one of the most important types [5]. Many ncRNAs have been verified to take crucial parts in transcriptional regulation, and regulation of proteins or RNA molecules [6]. The main classes of ncRNAs include long non-coding RNAs (lncRNA), microRNAs (miRNA), circular RNAs (circRNA), and Piwi-interacting RNAs (piRNA). NcRNAs can influence the health of the digestive system in terms of regulating gene expression, cell signaling pathways and epigenetic mechanisms. For example, ncRNAs can play a pro-inflammatory or anti-inflammatory role in the pathogenesis of IBD by modulating the function of inflammatory factors and immune cells [7]. In addition, altered miRNA expression has been associated with liver metabolic disorders, liver injury, liver fibrosis and other digestive system diseases [8]. More importantly, recent studies have shown that various ncRNAs regulate the biological mechanisms of DSCs, utilizing its complicated epigenetic regulatory mechanism as oncogenes or tumor inhibitor genes of upstream or downstream [9,10,11]. For instance, by competitively interacting with miR188-3p, lncRNA EIF3J-DT modulates the production of ATG14, which in turn activated autophagy and chemoresistance in gastric cancer [12]. In colon cancer, circPPFIA1s was downregulated and prevented colon cancer from metastasizing through the miR-155-5p/CDX1 and HuR/RAB36 pathways [13]. Besides, ncRNAs can themselves be regulated by epigenetic modifications and then play a crucial role in digestive cancers [14]. For example, in gastric cancer, demethylase ALKBH5 binding to m6A modification sites on lncRNA TP53TG1 to downregulate its expression, which promotes the progression of gastric cancer through the ALKBH5/ lncRNA TP53TG1/CIP2A/PI3K/AKT axis [15]. These findings underscore the critical role of ncRNAs in digestive cancers, and ongoing research is translating this knowledge into clinical applications [16].

Currently, research on epigenetic modification has been rapidly increased [17]. The wide range of covalent changes to nucleic acids and histone proteins that jointly control chromatin shape and gene expression is essential to the study of epigenetics [18]. Alterations in epigenetic modifications in cancer primarily involve three processes: abnormal DNA methylation, aberrant histone modifications (including methylation, acetylation, phosphorylation, ubiquitination), and dysregulated expression of various ncRNAs [19]. In recent years, there has been increasing research on histone modification, mainly focusing on histone methylation and histone acetylation modification [20, 21]. DNA in eukaryotic cells exists in chromatin, which is a large molecular complex composed of DNA, RNA, and proteins [22]. Histones, the primary protein components of chromatin, play a crucial role in DNA compaction and gene regulation [23]. Histones typically contain five components: H1, H2A, H2B, H3, and H4 [20, 24]. Except for H1, the other four histones bind to each other in dimers forming histone octamers to form nucleosome cores [25]. Various histone modifications alter the three-dimensional structure of nucleosomes, thereby influencing transcriptional control of associated genes [26]. Methylation frequently takes place on particular arginine (R) and lysine (K) residues on histone H3 and H4 [27]. Depending on the circumstances, histone lysine methylation can either activate or repress gene expression [28]. Histones can be modified by acetylation, which mostly affects the N-terminally conserved lysine residues [29]. For example, lysine residues 9, 14, 18, 23, and 27 in histone H3 and lysine 5, 8, 12, 16, and 20 in histone H4 can be acetylated [30]. Acetylation facilitates the separation of DNA from histone octamers and loosens nucleosome structures [31]. This process enables different transcription factors and co-transcription factors to bind to DNA binding sites in a specific manner, hence activating gene transcription [32, 33]. The opposite function is performed by histone deacetylation [34]. DNA methylation and various histone modifications can interact with one another [35]. fluctuations in the activity of histone-modifying enzymes often result in alterations associated with epigenetic diseases [36].

Recent research has demonstrated the critical role of ncRNAs in epigenetic alterations, regulating expression at both the gene and chromosome levels to control cell differentiation. Investigating the relationships between ncRNAs and histone modifications is important since they are crucial factors influencing the incidence and progression of digestive system cancers. Therefore, this article reviews the histone modification methods and their related ncRNAs in digestive system tumors in recent years, to investigate how they interact and how that affects the formation and incidence of malignancies in the digestive tract, including the biological mechanisms and clinical application of tumors. This work is intended to offer fresh perspectives on ncRNAs associated with histone modification, as well as therapeutic targets for the development of novel clinical diagnostic and prognostic indicators.

Histone modification

Extensive research has demonstrated that histone modifications are one of the most critical epigenetic mechanisms that influence chromatin-based reactions, thereby impacting gene expression and cancer progression, particularly in DSCs [37, 38]. Post- translational modification (PTM) is a crucial step in protein expression [39]. The post-translational modifications of histones occur at the N-terminal tails of histone proteins, and t includes acetylation (Ac), methylation (Me), phosphorylation (P), and ubiquitination (Ub) [40]. Among these, chromatin-modifying enzymes dynamically add or remove these covalently modified pathways on certain histone residues [41]. Histone acetylation is catalyzed by histone acetyltransferases (HATs), which enhance the accessibility of transcription factors to DNA, thereby promoting gene expression [42]. Conversely, histone deacetylases (HDACs) remove these acetyl groups, leading to chromatin condensation and gene repression [7, 43]. Aberrant HDAC activity has been associated with DSCs. Additionally, histone methylation involves the addition of methyl groups to lysine or arginine residues, mediated by histone methyltransferases (KMTs) and reversed by lysine demethylases (KDMs) [43]. Lysine methylation has a dual role, promoting gene activation (e.g. H3K4me3) or repression (e.g. H3K9me3, H3K27me3) [30, 44]. Lysine has three different methylation states (monomethylation, dimethylation, and trimethylation), and the degree of methylation is related to different transcriptional effects [44, 45]. Aberrant histone methylation leads to oncogene activation and tumour suppressor silencing [46], for example the PRC1 complex binds to trimethylated histone H3 Lys27 (H3K27me3) of the multi-combined repressor protein complex 2 (PRC2) creates a tight, transcriptionally repressed chromatin structure that ultimately leads to gene silencing, which is associated with the silencing of tumour suppressor genes [47]. Furthermore, written proteins called protein arginine methyltransferase (PRMT) can monomethylate or dimethylate arginine residues, leading to gene activation or inhibition [48, 49]. Various kinases and phosphatases phosphorylate and dephosphorylate histone residues that contain serine, threonine, and tyrosine, respectively [50]. Furthermore, phosphorylated residues can either mask binding sites for other reading proteins or provide binding sites for reading proteins [51]. Finally, histone ubiquitination occurs when three special enzymes, known as E1 activating enzyme, E2 coupling enzyme, and E3 ligase, connect small ubiquitin molecules containing 76 amino acids to lysine residues [52, 53]. Markers for ubiquitination can either stimulate or impede transcription [54]. The two obvious ubiquitination sites, for instance, are H2A Lys119 and H2B Lys120 [55]. The single ubiquitination of H2A Lys119 residues in the PRC1 complex causes gene suppression [56], whereas the ubiquitination of H2B Lys120 residues in the RNF20/40 complex leads to transcriptional activation [57]. In conclusion, the regulation of oncogenes and tumour suppressors can be affected by histone modifications, which indicates that histone modifications play a crucial role in the epigenetic regulation of gene expression in digestive tract cancers.

ncRNAs regulate histone modification in digestive system cancers (Fig. 1)

Fig. 1

Summary of histone modification related ncRNAs in DSCs. ncRNAs mainly include lncRNA, miRNA, circRNA, and piRNA. ncRNAs can directly regulate or be regulated by different types of histone modification, including methylation, acetylation, phosphorylation, and ubiquitination

The role of ncRNAs in cancer has been increasingly explored. Recently, many studies have confirmed that ncRNA can influence the progression of DSCs by actively regulating histone modifications (Fig. 2 and Table 1).

Fig. 2

ncRNAs directly regulate histone modification in DSCs. In HCC, lncRNA PVT1, lncRNA Hotair, lncRNA 01419, lncRNA MEG3, miR-144/451a, miR-20a, miR-101 regulate histone methylation; lncRNA SNHG14, lncRNA ZNF337-AS1, lncRNA CRNDE, miR-24-2 regulate histone acetylation; lncRNA CURD, miR-372 regulate phosphorylation. In CRC, lncRNA SATB2-AS1, lncRNA PiHL, lncRNA DLEU1 regulate histone methylation; lncRNA NEAT1, lncRNA HotairM1, lncRNA 00839, circACACA, circAGO2, miR-766-5p regulate histone acetylation. In GC, lncRNA SNHG22, lncRNA UC.145, lncRNA PART1 regulate histone methylation; lncRNA HOTAIR, circMRPS35 regulate histone acetylation. In ESCC, lncRNA ZNF667-AS1 regulate histone methylation; lncRNA TMPO-AS1, lncRNA 00886 regulate histone acetylation. In TSCC, miR-103a-2-5p regulate histone methylation. In NPC, lncRNA PVT1 regulate histone acetylation. In HNSC, lncRNA MX1-215 regulate histone acetylation. In GBC, lncRNA MALAT1 regulate histone methylation. In PAAD, lncRNA ZEB1-AS1, lncRNA PACERR regulate histone acetylation

Table 1 Histone modification regulate ncRNAs in DSCs

lncRNAs regulate histone acetylation in DSCs

LncRNA SNHG14 functions as an oncogene highly expressed in HCC dysregulation of lncRNA SNHG14 leads to H3K27ac enrichment in the promoter region of PABPC1, thereby positively regulating PABPC1 expression. Furthermore, PABPC1 functions as a downstream effector of SNHG14, which in turn regulates PTEN signaling [58]. Yuan et al. found that lncZNF337-AS1 was substantially expressed in HCC and was linked to H2A.Z and H2A.Zac controlled H2A's acetylation. The interaction between H2A.Z and KAT5 was considerably diminished when lncZNF337-AS1 was downregulated. Additionally, researchers also observed that H2A.Zac may alter the chromatin status and stimulate downstream genes transcription in HCC, which are critical regulators in the cancer misregulation cascade and include TCF3, CDKN1A, JUP, IGF1, CDK14, and SPINT1 [59]. Also in HCC, lncRNA CRNDE has been shown to be oncogenic. P300 belongs to the family of histone acetyltransferases that enhances EGFR promoter activity by acetylating H3K9 and H3K27, it increases EGFR expression through YY1 contact and YY1-mediated transcriptional regulation. LncRNA CRNDE acts as a marker of relaxed chromatin, which keeps the p300/YY1 complex steady at the EGFR promoter and also enhances acetylation of histones H3K9 and H3K27, which in turn alters the transcriptional regulation of downstream oncogenes [60].

In CRC, lncRNA NEAT1 is upregulated as a key component of the paranuclear nucleus, where it participates in transcriptional regulation [61]. Zhu et al. discovered that lncRNA NEAT1 elevated H3K27ac through chromatin remodeling, leading to enhanced acetylation of the promoter regions of c-Myc and ALDH1, which in turn elevated their expression and exerted an anti-cancer effect [62]. Zhang et al. discovered that lncRNA HotairM1 recruited EZH2 and SUZ12 to the promoter of HOXA1, the gene it targets, resulting in histone H3K27 trimethylation and inhibition of HOXA1 expression. As a result, the enhancer of the Nanog gene experiences H3K27 acetylation, which increases the production of Nanog and in turn represses HOXA1 expression, hereby establishing a new regulatory pathway that enhances stemness maintenance in CSC [63]. As a new oncogenic lncRNA in CRC, the study by Liu et al. revealed a novel functional mechanism by which lncRNA 00839 regulates NRF1 expression via chromatin epigenetic modification. LncRNA 00839 recruits Ruvb1 to the Tip60 complex and increases its acetylase activity. LncRNA 00839 directs the complex to the NRF1 promoter and promotes the acetylation of lysine 5 and 8 on histone H4, thereby upregulating NRF1 expression [64].

InGC, Song and colleagues demonstrated that the suppression of lncRNA HOTAIR resulted in a decrease in H3K27 methylation and an increase in H3K27 acetylation while H3K4 acetylation was reduced and H3K4 methylation was elevated. Prior research has demonstrated that methylation and acetylation of histone H3 lysine 27 function as antagonistic switches that regulate gene expression [65]. In this way, HOTAIR recruits EZH2 to induce methylation of H3K27 and decreases H3K27 acetylation in the presence of SUZ12. This inhibits CBP and H3K27ac binding, mediating the transition between H3K27 acetylation and trimethylation, which are linked to transcriptional activation and repression of the target genes, respectively [66].

In PC, lncRNA PACERR stimulates the KLF12/p-AKT/c-myc axis by binding to miR-671-3p. Liu et al. further demonstrated that in tumor-associated macrophages (TAMs), KLF12 binds to the promoter of lncRNA PACERR and increases enrichment of H3K27ac at the lncRNA-PACERR TSS. A co-immunoprecipitation assay later confirmed that KLF12 recruits the histone acetyltransferase EP300 and that lncRNA PACERR is necessary for the recruitment of EP300. It was finally concluded that in the nucleus, EP300 is enlisted by the KLF12/LncRNA-PACERR complex to facilitate lncRNA-PACERR transcription, forming a positive feedback loop [67]. In the same year, Liu et al. identified a novel epigenetic regulatory mechanism leading to the polarization of TAMs towards a protumor M2 phenotype. Histone acetyltransferase E1A-binding protein p300 is recruited to the promoter areas of PACERR and PTGS2 by CTCF-transcribed lncRNA-PACERR through direct interaction with CTCF. This process enhances histone acetylation and gene transcription and facilitates M2 polarization of TAM in PDAC [68]. Jin et al. illustrated that knockdown of lncRNA ZEB1-AS1 obviously increased HIF-1α acetylation and decreased HIF-1α and ZEB1 binding in hypoxic environments, demonstrating that ZEB1-AS1 stabilized HIF-1α through ZEB1-mediated deacetylation. Mechanistically, the connection among HIF-1α, ZEB1, and HDAC1 is mediated by lncRNA ZEB1-AS1. By promoting HDAC deacetylation activity, ZEB1 decreases HIF-1α acetylation, accelerating its stabilization [69].

The oncogenic lncRNA TMPO-AS1 has been reported to promote tumor progression by activating TMPO cis-transcription in ESCC. LncRNA TMPO-AS1 in ESCC cells is linked to fused in sarcoma (FUS) which recruited p300 to the promoter of lncRNA TMPO, forming biomolecular condensates that increase H3K27ac levels, thereby activating TMPO transcription in cis [70]. Moreover, lncRNA 00886 in ESCC interacts with SIRT7, reducing H3K18ac levels at the ELF3 promoter, thereby repressing its expression. Additionally, by attaching to the miR-144 promoter region, ELF3 can suppress the transcriptional activity of miR-144-3p in ESCC and increase the production of ZEB1 and ZEB2 [71].

In HNSCC, Ma et al. illustrated a novel IFNα-induced upregulated lncRNA, lncRNA MX1-215. A binding site for H3K27 acetylation exists at the promoters of PD-L1 and galactoglucan lectin-9. LncRNA MX1-215 directly interacts with the H3K27 acetylase GCN5 and interrupts its binding to H3K27 acetylation, and therefore, lncRNA MX1-215 negatively correlates with the expression of PD-L1 and galactoglucan lectin-9 [72].

In nasopharyngeal carcinoma (NPC), lncRNA PVT1 is upregulated. According to Wang et al. the chromatin-modifying factor KAT2A utilizes lncRNA PVT1 as a scaffold to mediate H3K9ac and recruit the nuclear receptor-binding protein TIF1β, which activates NF90 transcription. This increases the stability of HIF-1α and fosters a malignant phenotype in NPC cells [73].

lncRNAs regulate histone methylation in DSCs

Recent studies have revealed that lncRNA PVT1 is increased in HCC. Besides, lncRNA PVT1 disrupts the recruitment of EZH2 to the MYC promoter, and adversely controls EZH2 expression. Researchers discovered that PVT1 overexpression dramatically reduced the H3K27me3 level of this region and prevented EZH2 from recruiting to the MYC promoter [74]. Furthermore, lncRNA Hotair has been identified as a scaffold for PRC2 interactions, which results in chromatin remodeling and H3K27me3 [75]. Research has shown that Hotair attracted EZH2, an essential part of PRC2, in HCC cells [76]. Tian et al. showed that Curcumol markedly downregulated the lncRNA Hotair. Additionally, Curcumol reduced histone H3 methylation and EZH2 expression. LncRNA Hotair knockdown improved the growth inhibition produced by Curcumol and reduced EZH2 accumulation as well as H3K27 and H3K9 trimethylation. However, enhanced overexpression of Hotair enhanced this procedure and eliminated the growth inhibition caused by Curcumol in HCC [77]. Zhang et al. reported increased expression of LINC01419 in HCC, which may use H3K27me3 to lower the RECK expression level. Additionally, this work revealed that via binding to the H3K27me3 promoter of RECK, the LINC01419-EZH2 complex transcriptionally reduces RECK expression. Furthermore, EZH2-mRNA is stabilized by LINC01419 via a mechanism mediated by FUS, an RNA-binding protein (RBP) linked with oncogenesis that is involved in transcriptional control and RNA processing [78]. Jiang et al. indicated that lncRNA MEG3 is downregulated in human HCC. According to this study, MEG3 elevated the methylation modification of histone H3 (H3K27me1/2/3) at the 27th lysine in the promoter region of telomerase reverse transcriptase (TERT), which is dependent on the tumor suppressor gene P53. This inhibits TERT expression, subsequently reducing telomerase activity in HCC. HP1α, a heterochromatin protein involved in epigenetic alteration, is necessary for MEG3 to function [79]. Xu et al. found that lncRNA SATB2-AS1 decreased in CRC which served as a scaffold for WDR5 and GADD45A, cis-activating SATB2 transcription via facilitating the deposition of H3K4me3 and the demethylation of DNA in the SATB2 promoter region [80]. [Another study reported that lncRNA PiHL is substantially upregulated in CRC and interacts with EZH2 [81]. PiHL gives tumor cells chemoresistance and is triggered by downregulating KLF4. PiHL and EZH2 physically interact to modify H3K27me3 of HMGA2, which activates PI3K/Akt. Additionally, they showed that there may be an interaction between the G-quadruple motif placed in PiHL and the basic N-terminal helix of EZH2 [81]. Pang et al. demonstrated that hypomethylation leads to the high expression of lncRNA DLEU1 in colorectal carcinoma. LncRNA DLEU1 increases H3K27ac enrichment to the SRP4 site epigenetically, which in turn enhances SRP4 expression. Furthermore, through enhanced H3K4me3 and H3K27ac histone modification to its locus and decreased DNA methylation, epigenetic modification causes DLEU1 to be upregulated [82]. Mao, et al. found that transcriptional factor, ELK4 could bind to region of the lncRNA SNHG22 promoter and upregulate lncRNA SNHG22 expression in GC. Then lncRNA SNHG22 binds to EZH2 resulted in H3K27me3 accumulating at several tumor suppressor genes [83]. Yoon et al. demonstrated how the Wnt signaling pathway is triggered by the lncRNA UC.145, which interacts with EZH2 to cause DKK1 methylation. [The DKK1 promoter, a target of UC.145, contains an EZH2-binding site. Furthermore, the expression of global markers affected by H3K27me3 was downregulated upon suppression of lncRNA UC.145 expression [84].

In GC, lncRNA PART1 was found to be significantly downregulated. Mechanistically, promyelocytic leukemia zinc finger (PLZF) is upregulated following the interaction between PART1 and the androgen receptor (AR). The platelet-derived growth factor (PDGFB) promotor's enrichment of EZH2 and H3K27 trimethylation was enhanced by PLZF overexpression, thereby inhibiting PDGFB expression and suppressing the activation of the PDGFRβ/PI3K/Akt signaling axis [85].

Lin et al. found that lncRNA MALAT1 expression was elevated whereas ABI family member 3 binding protein (ABI3BP) expression was downregulated in GBC. The findings showed that MALAT1 might downregulate ABI3BP by recruiting EZH2 to the ABI3BP promoter region via H3K27 methylation [86]. In ESCC, it was discovered that lncRNA ZNF667-AS1 as well as ZNF667 were downregulated [87]. TET1 mediates the connection between histone changes and DNA methylation [88]. In DLD1 cells, decrease of TET1 boosted EZH2 and decreased UTX expression, which led to elevated H3K27me3 levels at the target gene promoter, resulting in gene repression [89]. It was suggested by researchers that lncRNA ZNF667-AS1 overexpression reduced H3K27me3 enrichment at the ZNF667 promoter region. Additionally, they discovered that ZNF667's mRNA expression level was considerably raised by overexpressing UTX or JMJD3. Moreover, the enrichment of H3K27me3 in the promoter of ZNF667 was dramatically reduced by overexpressing UTX or JMJD3, with the greatest effect occurring when UTX and JMJD3 were co-overexpressed. Furthermore, co-overexpression of ZNF667-AS1 and UTX reduced H3K27me3 enrichment at the ZNF667 promoter [87].

lncRNAs regulate histone phosphorylation in DSCs

In HCC, lncRNA CUDR forms a complex with P53 that binds to the promoter of PKM2, leading to increased PKM2 expression. Consequently, PKM2 binds to H3T11 which enhances the phosphorylation of histone H3(pH3T11). In addition, pH3T11 blocks the binding of HDAC3 to H3K9Ac, thereby preventing the deacetylation of H3K9Ac. On the other hand, it also decreases H3K9me3 and increases H3K9me1. Besides, H3K9me1 and Hp1α bind to form more H3K9me3-Hp1α complex, which binds to the promoter of Pim1 and enhances the expression of Pim1Pim1 subsequently increases TERT expression, which functions as the oncogene regulated by lncRNA HOTAIR, while simultaneously reducing the expression of TERRA [90].

miRNAs regulate histone modification in DSCs

In spite of the fact that lncRNA biogenesis plays crucial regulatory roles on histone modification in DSCs progression, microRNAs were also found closely connected to histone modification in DSCs progression. More importantly, lncRNAs and miRNAs can play an important role in the regulation of histone modifications through complex interactions. lncRNAs can adsorb miRNAs as ceRNAs, thereby enhancing or inhibiting the regulatory effects of miRNAs on HATs or HDACs thereby regulating histone acetylation. In addition, miRNAs can indirectly regulate histone modification by repressing certain transcription factors, whereas lncRNAs can directly interact with these factors. In summary, aberrant interactions of lncRNAs and miRNAs lead to disorders in histone modification, which in turn affects the expression status of tumour suppressor genes and oncogenes in DSCs.

miRNAs regulate histone acetylation in DSCs

MiR-24-2 targets and inhibits PRMT7, reducing the dimethylation and trimethylation of arginine-3 on histone H4 on the promoter of the lncRNA HULC, and therefore enhances the expression of lncRNA HULC. LncRNA HULC subsequently promotes Nanog expression. Furthermore, Inhibition of histone deacetylase HDAC3 by miR24-2 via miR-675 promoted acetylation modification of Histone H4 lysine 16th position in human hepatocellular carcinoma stem cells [thereby increasing PI3K expression and inducing cellular autophagy [91]. High levels of H3K27ac, catalyzed by the extremely homologous histone lysine acetyltransferases CREB binding protein (CBP), are a feature that most super-enhancers (SE) share [92, 93]. Tumor-specific SEs are commonly acquired by cancer cells at important oncogenes (e.g., MYC). MiR-766-5p inhibits CBP in CRC, which lowers the H3K27ac level of MYC SEs and downregulates the expression of MYC [94].

miRNAs regulate histone methylation in DSCs

Based on reports, histone methylation modulates the expression of several genes linked to metastasis and proliferation in HCC [95]. In recent research, miR-144 targeted EZH2, and PRC2 epigenetically suppressed the miRNA genes by H3K27 methylation of the promoter in HCC, creating a negative feedback loop that downregulates boththe miR-144/miR-451a cluster and EZH2 [96]. Zhang, et al. demonstrated that miR-20a downregulation directly targeted EZH1's 3′UTR and suppressed EZH1 expression in HCC. Additionally, researchers revealed that the expressions of H3K27me, H3K27me2, and H3K27me3 increased in HCC [97]. Researchers demonstrated zinc-finger protein 217 (ZNF217) was a target gene of miR-101 in HCC. Knockdown of ZNF217 or LSD1 resulted in increased H3K4me2 levels at the CDH1 promoter. ZNF217 and LSD1 knockdowns consistently resulted in more noticeable alterations to CDH1 mRNA expression. Together, these factors reduced the inhibitory effects of miR-101 on HCC malignant behaviors. Overexpression of ZNF217 could accelerate HCC progression by recruiting LSD1 to reduce H3K4me2 levels at the CDH1 promoter, thereby inhibiting CDH1 transcription [98]. Liu, et al. demonstrated that lncRNA LTSCCAT is a competing RNA for the modulation of miR-103a-2-5p in TSCC. SMYD3 is a histone methylation transferase that plays a crucial role in transcriptional control and is able to dimethylate or trimethylate proteins. Investigations have indicated that miR-103a-2-5p binds to the 3′-UTR of SMYD3 and prevents its translation. SMYD3 binds to the promoter of TWIST1 and promotes its transcription, promoting its transcription through H3K4me3 [99].

miRNAs regulate histone phosphorylation in DSCs

In HCC, miR-372 enhances CTCF expression by directly targeting genes homologous to phosphatases and tension proteins PTEN. Meanwhile, CTCF turns HULC, a highly upregulated lncRNA in hepatocellular carcinoma, into a cyclic RNA, which in turn promotes the phosphorylation of Y box binding protein-1 (YB1). Further pYB1 binding to β-catenin significantly inhibits the ubiquitination degradation of β-catenin, thereby enhancing PKM2 expression and activity. PKM2 further promotes the acetylation of lysine 9 on histone H3 (H3K9Ac). Finally, H3K9ac modification of the promoter region of the oncoprotein erbB2 is significantly increased in miR-372 overexpressing human hepatocellular carcinoma cells and further enhancing erbB2 expression [100].

circRNAs regulate histone modification in DSCs

circRNAs regulate histone acetylation in DSCs

CircRNA is a class of covalently closed endogenous non-coding RNA that can act as a molecular sponge, sequestering specific miRNAs that are known to regulate histone-modifying enzymes, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases. By modulating these miRNAs, circRNAs can indirectly influence histone acetylation and methylation, thereby activating or repressing gene transcription. Its regulation of histone modifications and epigenetic changes plays an important role in diseases such as cancer. Zhu et al. found that circAGO2 is upregulated in CRC and functions as an oncogene. Additionally, RBBP4 is thought to be a component of protein complexes involved in several chromatin modifications, in particular the histone deacetylase complex [101], which inhibits H3K27ac at the promoter region of HSPB8 and therefore represses the gene expression in CRC. In conclusion, circAGO2 attenuates miR-1-3p-induced RBBP4 repression, thereby targeting RBBP4 to repress HSPB8 transcription [102]. In CSC, circACACA promotes HDAC3 expression by sponging miR-193a/B-3p. HDAC3 induces p53 deacetylation to inhibit p53-induced apoptosis, increasing the levels of mevalonate (MVA) pathway-related molecules, including SREBP2, HMGCS1, HMGCR, ACAT2, and MVK [103]. In gastric carcinoma, circMRPS35, a novel scaffolding chaperone for KAT7, specifically recruits KAT7 to the FOXO1 and FOXO3a gene promoters, increasing the expression of H4K5ac in the promoter regions of the target genes. In addition, circMRPS35 binds directly and specifically to the FOXO1/3a promoter region, [activating their transcription and inducing the expression of downstream genes such as p21, p27, Twist1, and E-cadherin [104].

ncRNAs are regulated by histone modification in DSCs (Fig. 1)

Excepting from directly regulating histone modification, ncRNAs also could be modulated by histone modifications in DSCs (Table 2).

Table 2 ncRNAs regulated by histone modification in DSCs

lncRNAs are regulated by histone modification in DSCs

lncRNAs are regulated by histone acetylation in DSCs

Zhuang et al. identified a novel lncRNA, lnc-Ip53, which is induced and expressed by p53and found that lnc-Ip53 could bind to histone deacetylase HDAC1 and histone acetyltransferase p300, respectively, inhibiting p300 activity. On one hand, it prevents HDAC1 degradation, on the other hand, it leads to an increase in the level of HDAC1. Ultimately synergistically inhibiting the acetylation of p53 [105]. Liu et al. found that lncRNA EIF3J-AS1 is upregulated through cAMP response element binding protein-mediated H3K27ac in its promoter region. Besides, lncRNA EIF3J-AS1 upregulates YAP1 level through sponging miR-3163 in CRC [106]. LncRNA LOC101928316 served as a tumor inhibitor gene to affect the progress of GC by the activation of the PI3K/Akt/mTOR pathway. As a deacetylation transferase, HDAC3 was proven to significantly downregulate the acetylation levels of gene promoters, thereby suppressing gene transcription. In gastric cancer cells, HDAC3 reduces H3K14ac recruitment by suppressing the acetylation at the LOC101928316 promoter, thereby suppressing the transcription of LOC101928316 [107]. Consistent with the above, lncRNA-LET acts as an oncogene, which can be transcriptionally repressed by HDAC by decreasing the expression of histone acetylation in the promoter region. Furthermore, lncRNA-LET sponges miR-548 k in GC. Consequently, HDAC3 regulates the progression of GC via the lncRNA-LET/miR-548 k axis [108]. In pancreatic cancer, Li et al. revealed a downregulated ncRNA-lncRNA ZNFTR. LncRNA ZNFTR is a hypoxia suppressing lncRNA through the HIF-1α and HDAC1 complex depending on deacetylation of the promoter. Therefore, the transcription of lncRNA ZNFTR is suppressed by the HIF-1α/HDAC1 complex mediated deacetylation [109]. In pancreatic cancer, HAT1 enhances lncRNA PVT1 expression by promoting BRD4 binding to the lncRNA PVT1 promoter. Mechanistically, HAT1 catalyzes H4 acetylation and BRD4 acts as a transcriptional activator for binding to histone H4, thus regulating PVT 1 expression [110]. CREB-binding protein (CBP), a HAT that predominantly acetylates H3 histones, plays a key role in chromatin acetylation [34]. Identically, the levels of CBP and H3K27ac in the lncRNA LOC146880 promoter are significantly elevated and therefore lncRNA LOC146880 is activated transcription in ESCC. Furthermore, lncRNA LOC146880 acts as ceRNA for specific miRNAs modulates the expression of miR-328-5p. Ultimately, LOC146880 functions as a sponge of miR-328-2p upregulating the activation of FSCN1 and MAPK pathway, thus influencing the progression of ESCC [111]. Similarly, CBP, is also correlated with the progression of OSCC. LncRNA PLAC2 is found to be upregulated in OSCC. CBP-mediated H3K27ac modification in the promoter of lncRNA PLAC2 induces upregulation of PLAC2, which promotes malignant progression of OSCC through activation of the downstream Wnt/β-catenin pathway [112]. In TSCC, CBP can also mediate the recruitment of H3K27ac in the promoter region to upregulate the downstream oncogene lncFOXC2-AS1. Immediately following this, LncFOXC2-AS1 functions as a ceRNA, increasing E2F3 expression by sponging miR-6868-5p [113]. In hepatocellular carcinoma, the expression of histone HDAC2 can be inhibited under appropriate conditions, therefore the decrease of HDAC2 can upregulate the histone acetylation expression of the promoter of lncRNA MIR22HG. Furthermore, the expression of MIR22HG and miR-22-5p derived from MIR22HG were elevated [114]. LncRNA ANCR is abnormally upregulated as an oncogene in HCC. Wen et al. found that the H3 and H4 histone acetylation levels of the ANCR promoter were upregulated, thus determining that ANCR expression in HCC is regulated by histone acetylation at the promoter and that interfering HDAC3 significantly upregulated ANCR expression. In addition, lncRNA ANCR upregulates HNRNPA1 expression through uptake of miR-140-3p. Next, siANCR promotes the ubiquitination of HNRNPA1, such a result suggests that ANCR inhibits the degradation of HNRNPA1 by inhibiting its ubiquitination [115].

lncRNAs are regulated by histone methylation in DSCs

Huang, et al. illustrated that downregulation of lncRNA GMDS-AS1 was in regulation of ESET in HCC. H3K9 histone methyltransferase ESET is a particular enzyme that catalyzes H3K9 methylation. The research found that the level of [H3K9me1 levels significantly decreased after EZH2 downregulation. According to the experiment, H3K9me1 bound to the GMDS-AS1 promoter increases in HCC. Furthermore, GMDS-AS1 expression was significantly elevated by ESET silencing in HCC. Collectively, studies showed that lncRNA GMDS-AS1 expression in HCC was suppressed by ESET-mediated H3K9me1 enrichment on the GMDS-AS1 promoter. Additionally, they confirmed that GMDS-AS1 is directly bound to proteasome subunit beta type-1 precursor (PSMB1), hence adversely regulating it [116]. LncRNA MALAT1 is upregulated in CRC. In CRC, nuclear translocation of JMJD2C decreased the histone methylation levels at the MALAT1 promoter. Wu, et al. indicated that JMJD2C is bound to the lncRNA MALAT1 promoter and modulates the histone methylation level at the H3K9m3 and H3K36m3 sites of the MALAT1 promoter. Additional experiments provided evidence that JMJD2C stimulated the promoter activity of the MALAT1 gene and enhanced its transcription. The aforementioned findings indicated that JMJD2C might translocate into the nucleus, modulate the MALAT1 promoter’s histone methylation level, and increase MALAT1 expression [117].

miRNAs are regulated by histone modification in DSCs

miRNAs are regulated by histone acetylation in DSCs

MiR-34a acts as a tumor inhibitor in HCC, but upregulation of lncRNA 34a decreases miR-34a in HCC. [This inhibition of miR-34a by lnc34a is achieved through increased methylation of the miR-34a promoter and reduced association of acetylated histones H3 and H4. Besides, miR-34a modulated TGF-β signal pathway by targeting Smad4, followed by regulating the downstream genes transcription [118]. Wang et al. identified a novel miRNA, miR-1185-1, which acts as an oncogene to inhibit CD24 expression by targeting the 3’UTR of CD24. Histone modifications in the promoter region of miR-1185-1 were detected, and it was found that SIRT1 reduces H3K9ac on the miR-1185-promoter, which in turn induces chromatin remodeling to suppress miR-1185-1 expression [119, 120].

miRNAs are regulated by histone methylation in DSCs

In HCC, EZH2 is aberrantly upregulated and suppresses the expression of miR-381. Mechanistically, EZH2 can bind to miR-381, and its overexpression enhances the expression of H3K27me3 on the promoter of miR-381. Collectively, miR-381 targets SETDB1, but EZH2-mediated suppression of miR-381 results in increased SETDB1 levels. SETDB1, a histone methyltransferase, promotes the methylation of AKT at the K64me3 locus, which activates phosphorylation at T308 and S308 inhibitory sites which in turn is involved in HCC progression [121]. MiR-1224 is downregulated in HCC. By binding to cAMP-response element binding protein (CREB), miR-1224 inhibits the transcription and activation of the YAP signal pathway. In addition, EZH2 mediates H3K27me3 at the miR-1224 promoter. CREB represses miR-1224 expression, resulting in a positive feedback circuit [122]. Tian et al. indicated that the downregulation of tumor inhibitor miR-124 mainly owing to hypermethylation of the promoter of this gene in ESCC. Mechanistically, histone methyltransferase EZH2 directly targets miR-124-3p by H3K27me3, which leads to decreased miR-124-3p expression [123]. Guo et al. found abnormal upregulation of CDK11B and downregulation of SPDEF in HCC, which was attributed to the fact that CDK11B can downregulate SPDEF expression through CDK11B via upregulation of SPDEF phosphorylation and ubiquitin dependent degradation. SPDEF can bind to miR-448 promoter and inhibit DOT1L expression by activating miR-448. MiR-448 binds to the 3′-UTR of DOT1L mRNA and negatively regulates its expression [124].

circRNAs are regulated by histone modification in DSCs

circRNAs are regulated by histone acetylation in DSCs

CircSOD2 is significantly upregulated as an oncogene in HCC. In HCC, the circSOD2 promoter's H3K27ac and H3K4me3 alterations are elevated by WDR5 and EP300 enrichment. Moreover, circSOD2 suppresses the expression of miR-502-5p by serving as a sponge for it, which in turn increases the expression of DNMT3a. By suppressing SOCS3 expression and promoting SOCS3 promoter hypermethylation, DNMT3a-mediated DNA hypermethylation speeds up the downstream activation of the JAK2/STAT3 signaling pathway [125].

Biological effects of ncRNAs on DSCs

Currently, it's thought that histone modification is considered a crucial factor in genetic alterations and the inactivation of tumor-related genes [126]. So far, an abundance of genes relevant to various biological processes have been shown to be related to histone modification in digestive cancers Fig. 3 and Table 3).

Fig. 3

Summary of biological mechanisms of histone modification related ncRNAs in DSCs. The crosstalk between ncRNAs and histone modifications can affect cell function mainly concentrating on proliferation, invasion, metastasis, angiogenesis, cell cycle arrest, EMT, and apoptosis

Table 3 Biological mechanisms of histone modification related ncRNAs in DSCs

For instance, lncRNA SNHG14 promotes tumorigenesis of HCC and cell proliferation, migration, and angiogenesis via upregulating PABPC1 through H3K27 acetylation [58]. In HCC, increased levels of H3 histone acetylation at the lncRNA ANCR promoter upregulate lncRNA ANCR expression. Furthermore, lncRNA ANCR promotes HNRNPA1 expression by sponging miR-140-3p and promotes the epithelial-mesenchymal transition (EMT), invasion and migration of HCC cells via up-regulating HNRNPA1 expression [115]. Additionally, epigenetic inhibition of lncRNA GMDS-AS1 by methyltransferase ESET promotes tumorigenesis and tumor cells proliferation, tumor cells proliferation is usually accompanied by cell invasion and migration, and long non-coding RNAs like these affect tumor cells invasion and migration [116]. In CRC, Liu et al. demonstrated that lncRNA 00839 promoted acetylation of lysine 5 and 8 of histone H4 and upregulated NRF1, which promoted proliferation, invasion and metastasis of CRC cells [64]. In contrast, lncRNA SATB2-AS1 exerts its biological effects by targeting SATB2 to inhibit proliferation, metastasis, and invasion of CRC cells [80]. In gastric cancer, the ability of lncRNA UC.145 to promote cancer cells growth and migration, invasion and colony formation by interacting with EZH2 to induce DKK1 methylation, thus participating in the Wnt signaling pathway [84]. Zhang et al. found that HDAC3 was significantly overexpressed in GC cells lines and promoted proliferation, invasion and migration of tumor cells while inhibiting apoptosis through inhibition of histone acetylation in the promoter region of lncRNA-LET and subsequent down-regulation of lncRNA-LET expression [108]. LncRNA-PACERR promotes pancreatic cancer tumorigenesis with proliferation, invasion and migration of tumor cells while lncRNAZNF24 inhibits the proliferation, metastasis and pro-angiogenic capacity of pancreatic tumor cells by suppressing the transcription of vascular endothelial growth factor A(VEGFA) [67, 109].

Both miRNAs and circRNAs, important components of ncRNAs, play key regulatory roles in the biological functions of DSCs. According to reports, miR-24-2 has been shown to be dependent on the expression of the autophagy-related tumor gene Src., which in turn promotes the proliferation, migration, invasion and metastasis of tumor cells [125]. Zhang et al. demonstrated that miR-20a targeted targeting attenuated EZH1 expression and suppressed HCC proliferation and metastasis by reducing H3K27 methylation [97]. Moreover, miR-101 acts as a negative regulator of ZNF217, and by inhibiting the expression of ZNF217 can restrain the epithelial-mesenchymal transition of HCC cells, thus attenuating HCC cells proliferation and invasion [98]. Also in HCC, Yang et al. demonstrated that epigenetically regulated miR-1224 induced hepatocellular carcinoma cells to arrest in the G0/G1 phase and inhibited HCC proliferation through CREB-mediated activation of the YAP signaling pathway [122]. Besides, EZH2 inhibits miR-381 expression by promoting H3K27me3 activity in the promoter region, which enhances the expression of SETDB1, thereby activating the AKT pathway to promote hepatocellular carcinoma cells proliferation and migration [121]. In addition, Zhu et al. showed that miR-124-3p acted as a negative regulator to inhibit ESCC cells proliferation, migration and invasion by directly targeting EZH2 [123]. Also in HCC, circSOD2 acts as a sponge to inhibit the expression of miR-502-5p, which promotes tumor cells progression, migration, cell cycle, and tumorigenesis through the activation of the downstream JAK2/STAT3 signaling pathway [125]. Zhu et al. demonstrated that circAGO2 overexpression induced miR-1-3p to increase RBBP4 expression to promote CRC cells proliferation and invasion [102]. Similarly, circACACA promotes CRC growth and metastasis by sponging miR-193a/b-3p to stimulate the HDAC3/MVA pathway [103]. In gastric cancer, Jie et al. demonstrated that circMRPS35 inhibited tumorigenesis by controlling histone modification through the recruitment of KAT7 and inhibited the proliferation and migration of tumor cells through the circMRPS35/KAT7/FOXO1/3a pathway [104].

Clinical application of ncRNAs in DSCs

With further research into epigenetic modifications of ncRNAs, various new targets have been confirmed to be involved in the occurrence and development of DSCs [127]. Moreover, recent studies suggest that histone-modified ncRNAs can serve as valuable biological markers for the diagnosis and treatment of DSCs. Owing to its resistance to chemotherapy drugs, it can be targeted for clinical chemotherapy resistant patients (Fig. 4 and Table 4).

Fig. 4

Clinical application of histone modification related ncRNAs in DSCs. Clinical potential on histone modification related ncRNAs in DSCs is reflected in chemoradiation resistance, prognosis biomarkers, diagnosis biomarkers, and treatment targets

Table 4 Clinical application of histone modification related ncRNAs in DSCs

ncRNAs regulate chemoradiation resistance

One of the factors contributing to poor prognosis and recurrence in cancer patients is chemoresistance [128]. Evidence has been presented that resistance to chemotherapy may have an epigenetic basis [129]. In hepatocellular carcinoma, lncRNA CRNDE expression induces sorafenib resistance through EGFR-mediated signaling. Mechanically, Sorafenib resistance results from the epigenetic p300/YY1 complex's positive upregulation of EGFR, which is dependent on CRNDE expression. In general, p300 inhibitors, for instance, C646 might offer an effective substitute treatment choice for individuals with advanced HCC who are resistant to sorafenib [60]. Additionally, lncRNA NEAT1 NEAT1 is associated with resistance to 5-fluorouracil (5-Fu) in CRC. NEAT1 influences 5-Fu resistance in CRC by affecting cancer stem cells Therefore, the study proposes that to treat CRC patients with high levels of NEAT1, chemotherapy should be combined with medications that target tumor stem cells [62]. Similarly in CRC, lncRNA PiHL was found to be induced by the downregulation of KLF4, conferring resistance to oxaliplatin. Mechanically, PiHL binds to EZH2 and regulates H3K27me3 of HMGA2, leading to activation of PI3K/Akt pathway. To overcome oxaliplatin resistance, lncRNA PIHL may function as a therapeutic target, improving the clinical advantages of oxaliplatin treatment in colorectal cancer patients [81]. Ren et al. found that the downregulation of LOC101928316 by HDAC3 promoted gastric cancer resistance to cisplatin by influencing the PI3K/Akt/mTOR pathway, which provided a theoretical basis for LOC101928316 to treat chemoresistance in gastric cancer [107]. In pancreatic cancer, aberrant HAT1 level promotes gemcitabine resistance, whereas silencing HAT1 restores gemcitabine sensitivity, and the mechanism of HAT1-mediated chemoresistance is modulated by PVT1 and EZH2. In conclusion, HAT1 as a potential target for therapy targeting HAT1 therapy significantly increases the pancreatic cancer cells’ sensitivity to gemcitabine [110]. In addition, in HCC, upregulation of miR-381 expression inhibited AKT pathway activation, with the downregulation of lnc-Ip53 being both used in anticancer therapy to inhibit hepatocarcinogenesis and chemotherapy resistance [105, 121]. In addition to chemotherapy, radiotherapy is also a clinical challenge that requires attention, so identifying new cancer radiosensitization targets may provide more potent therapeutic strategies for radiotherapy. Irradiation upregulates MIR22HG expression and downregulates HDAC2, and mechanistically, by upregulating MIR22HG expression and promoting the histone acetylation promoter area, suppression of HDAC2 expression raises radiosensitization in HCC through miR-22-5p. Thus, the finding will facilitate the discovery of novel targets for cancer radiation treatments [114]. Besides, another main treatment for NPC is radiation. Since LncRNA PVT1 interferes with TIF1β and H3K9ac’s interaction to reduce the radiosensitivity of nasopharyngeal cancer cell lines, PVT1 could potentially serve as a therapeutic target in clinical trials [73].

ncRNAs as cancer biomarkers and therapeutic targets in DSCs

In different digestive tumors, ncRNAs play a very important role, and studies on their functions and mechanisms has demonstrated their potential for clinical applications, mainly focusing on diagnostic, prognostic, and therapeutic biomarkers.

In the clinical specimens of HCC, high expression of lncZNF337-AS1 predicted poor patient outcomes, whereas downregulation of miR-144/miR-451a cluster was associated with improved patient prognosis [59, 96]. Besides, metastasis, a key factor in poor prognosis, is often observed in HCC, with common sites including the lungs and bones etc. Zhang et al. found that Lnc34a was associated with bone metastasis by modulating miR-34a expression through promoter methylation and histone deacetylation [118]. In addition, high expression of LINC01419, ANCR and down-regulation of miR-1224 correlated with poor clinicopathological characteristics, including larger tumor size, poorer differentiation, portal vein tumor thrombus, and advanced clinical stage [78, 115, 122]. These findings provide a theoretical foundation for the diagnosis, treatment, and prognostic estimation of HCC as well as for treatment and prognostic estimation.

In CRC, HotairM1 is downregulated and serves as a positive prognostic factor for patients, while upregulation of LINC00839 and DLEU1 expression are correlated with worsening prognosis. High expression of LINC00839 and lncRNA DLEU1 are correlated with distant metastasis, lymph node involvement, TNM stage, vascular invasion, and advanced clinical stage, these results indicating that increased expression of these lncRNAs is linked to CRC metastasis and lower survival probability [63, 64, 82]. Besides, Wang et al. noticed miR-1185-1 has been identified as a tumor suppressor, with miR-1185-1 mimics offering a promising approach for targeted therapy against the tumor microenvironment immunosuppression and cancer stemness in colorectal cancer [119].

lncRNA HOTAIR, lncPART1, and circMRPS35 have been identified as potential biomarkers for metastasis, prognosis, and overall survival in GC. As an oncogene, HOTAIR is upregulated and linked to various clinicopathological factors, including lymph node metastasis, TNM stage, and venous invasion. Differently, both circMRPS35 and lncPART1 exhibit an inverse correlation with tumor growth, lymphatic metastasis, and advanced TNM stage [66, 104]. Additionally, a study found that the interaction of UC.145 with DKK1 and another lncRNA, PRKG1-AS1, had a synergistic effect on the Wnt pathway in cancer and that the modulation of genes above was strongly correlated with overall patient survival [84]. Mao et al. found that lncRNA SNHG22 promotes GC progression by regulating miR-200c-3p/Notch1 axis. Therefore, SNHG22 is a potential biomarker for diagnostic and prognostic targets for GC therapy [83].

In pancreatic cancer, downregulation of ZNFTR is correlated with lymphatic infiltration, TNM stage, distant metastasis and vascular infiltration. Besides, Kaplan–Meier survival analysis indicates that ZNFTR overexpression is associated with longer overall survival [109]. Similarly, dysregulated expression of ZEB1 is linked to distant metastasis, lymphatic metastasis, and histological grade in PC patients [69].

Tian et al. illustrated that miR-124 was downregulated in ESCC, suggesting a poor prognosis and reduced survival of ESCC patients. Researchers found that the methylation status of miR-124-1 and miR-124-3 was found to be correlated with histological grade and TNM stage [123]. Also, in ESCC, Dong et al. illustrated that the levels of ZNF667-AS1 and ZNF667 expression levels were associated with distant metastasis, recurrence, pathological differentiation degree, lymph node metastasis, and TNM stage. Besides, ESCC patients with lower expression of ZNF667-AS1 or ZNF667 had a significantly lower 5-year survival rate [69]. In addition, the expression of TMPO-AS1 and LOC146880 are upregulated in ESCC, and their overexpression is related to shorter overall survival time [70, 111]. In contrast, the lower expression level of LINC00886 in ESCC is correlated with TNM staging and lymph node metastasis [71].

Advances in understanding aberrant ncRNA epigenetic alterations in gastrointestinal tumors may provide novel biomarkers] for clinical diagnosis, prognosis, and therapeutic applications.

Discussion

Increasing evidence suggests that histone modifications play an irreplaceable role in cancer regulation. In parallel with the rapid advancement of transcriptomics, the role of ncRNA in digestive tumors is becoming progressively clearer. The relationship between ncRNA and histone modifications, two significant epigenetic regulatory components, has been shown to be critical in controlling the malignant biological behavior of digestive tract cancers, affecting tumor patient resistance to radiotherapy and chemotherapy, and survival prognosis. However, a comprehensive summary of the relationship between ncRNAs and histone modifications in digestive tumors is still lacking.

In this review, we mainly discussed the relationship between ncRNAs and histone epigenetic modifications in digestive tract tumors, and how these two elements interact to influence clinical prognosis, the biological behavior of malignancies, and resistance to chemotherapy and radiotherapy. NcRNAs regulate histone modifications, impacting gene regulation and mediating chromatin formation. On the contrary, epigenetic modifications of histones can also modulate the synthesis, degradation, transcription, and processing of ncRNAs. In addition, ncRNAs can also influence the activity of histone-modifying enzymes, further affecting the expression and function of downstream proteins in cancer. In summary, we found that up to now, the regulation of histones related to ncRNAs is mostly limited to crosstalk between lncRNAs, miRNAs, and histone methylation and acetylation, while crosstalk between ncRNAs and phosphorylation and ubiquitination is relatively rare. This may be due to the fact that histone phosphorylation and ubiquitination involving related regulatory enzymes or signaling pathways are not well studied and that the process is rapid and reversible, making it difficult to detect experimentally. With the continuous development of ncRNAs research, scholars have begun to study the relationship between circRNAs and histone modifications in gastrointestinal tumors. However, the role of emerging piRNAs in this context remains unexplored. NcRNAs and histone modifications can form feedback loops that regulate key biological behaviors of tumor cells, such as proliferation, invasion, metastasis, and apoptosis, by influencing different cellular signaling pathways. In addition, certain stably expressed histone-modified ncRNAs have shown potential as prognostic, therapeutic, and diagnostic indicators in clinical trials. However, research on the role of histone modifications in ncRNA-mediated resistance to radiotherapy and chemotherapy in gastrointestinal cancers remains limited. Moreover, ncRNAs are critical regulators in maintaining the homeostasis of a healthy digestive system. Beyond their well-established role in cancers, they widely influence and participate in the physiological and pathological processes of digestive diseases. For example, miRNA and lncRNA are key roles in modulating inflammatory responses, which is crucial in conditions like inflammatory bowel disease. Additionally, certain lncRNA is involved in the onset and progression of liver injury, holding significant regulatory roles in liver diseases such as viral hepatitis and liver fibrosis. Given its critical role, further exploration of ncRNAs in clinical applications could greatly enhance our understanding of gastrointestinal diseases and improve patient outcomes.

We believe that research on the function and mechanism of histone-modified ncRNAs in digestive system tumors, ultimately, will help identify useful targets for the treatment of DSCs. This will facilitate the discovery of novel clinical biomarkers and provide new treatment strategies for managing digestive tract cancers.